This project will target the enzyme, fatty acid synthase (FAS), for the chemoprevention of lung cancer. Our preliminary studies have found that the vast majority of non-small cell lung cancers express much higher levels of this enzyme than normal tissues, and that this increased expression of FAS occurs relatively early in lung cancer development. Furthermore, inhibition of this enzyme in neoplastic cells leads to a metabolic imbalance and cellular apoptosis. In preliminary experiments, we found a promising anti-tumoral response when treating human lung cancer orthotopic nude rat xenografts with an FAS inhibitory compound. Importantly, these treatments did not result in any recognizable damage to normal tissue but did lead to doselimiting anorexia. The studies proposed in this application will develop the use of FAS inhibitory therapy for lung cancer chemoprevention. In the first aim of our preclinical studies, we will compare several novel FAS inhibitory agents that show less anorectic effects than C-75 to identify a lead compound with high level of anti-neoplastic activity and minimal toxicity. These experiments will examine activity of candidate compounds against human lung cancer cell lines and lung cancer explants in vitro, and against lung cancer xenografts in vivo to assure that the selected compound has activity against a broad range of human lung cancer phenotypes. In the second phase of these preclinical studies, we test this lead compound for ability to prevent tumorigenesis in A/J mice that have been exposed to the tobacco specific carcinogen, 4-(methylnitrosamino)-l-(3-pyridyl)-1-butanone (NNK). To optimize the chemoprevention protocols in this mouse model of lung carcinogenesis, we will use positron emission tomography (PET) imaging to monitor tumor development and response of tumors to the metabolic inhibitor. This optimization of treatment protocols could be useful for designing treatment protocols to be applied in the clinical setting, potentially coupled with PET imaging for monitoring efficacy. The third aim of this project is to examine the effects of the FAS inhibitory compound when used in combination with other agents, such as those currently being considered for chemoprevention of lung cancer. Because the FAS target represents a pathway distinct from those targeted by other compounds, there is a significant potential that such combinations could have synergistic antineoplastic activity. Furthermore, a combination of agents is likely to have activity against the development of a broader range of lung cancer phenotypes than individual agents. Successful completion of these preclinical studies will provide a framework for further evaluation of an FAS inhibitory compound for the chemoprevention of lung cancer in the clinical setting.